As the use of conventional pharmaceutical antibiotics has increased for medical, veterinary and agricultural purposes, there has been a concurrent emergence of antibiotic-resistant strains of pathogenic bacteria.
The emergence of single- or multi-drug resistant bacteria can result from a gene mobilization that responds to selective pressures associated with antibiotic use. Over the last several decades, the increasingly frequent usage of antibiotics has acted in concert with spontaneous mutations arising in the bacterial gene pool to produce different strains of bacteria not susceptible to current antibacterial treatments. This repertoire of antibiotic resistant genes can be utilized by previously sensitive strains that have access to these genes (e.g., via conjugative transfer of plasmids or transposons). As a result, single- and multi-drug resistance genes are commonly found in a large variety of bacterial plasmids and conjugative transposons.
Gram-positive bacteria are a major cause of nosocomial infection. The most common pathogenic isolates in hospitals include Enterococcus spp., Staphylococcus aureus, coagulase-negative staphylococci, and Streptococcus pneumoniae (See, e.g., Principles and Practice of Infectious Diseases, 4th ed. Mandell G L, Bennett J E, Dolin R, ed. Churchill Livingstone, New York 1995), many strains of which are resistant to one or more antibiotics. Enterococcus spp. are part of the normal gut flora in humans. Of the more than seventeen enterococcal species, only E. faecalis and E. faecium commonly colonize and infect humans in detectable numbers (E.faecalis is isolated from approximately 80% of human infections, and E. faecium from most of the rest).
Vancomycin-resistant enterococcus (VRE) spp. are becoming increasingly common in hospital settings. In the first half of 1999, 25.9% of entercoccal isolates from Intensive Care Units were vancomycin-resistant; an increase from 16.6% in 1996 and from 0.4% in 1989. VRE are also commonly resistant to many other commercial antibiotics, including beta-lactams and aminoglycosides. Thus, patients who are immunocompromised or those having a prolonged hospital stay are at increased risk for acquiring a VRE infection.
The problem of antibiotic resistance is not unique to Enterococcus spp. Strains of many other potentially pathogenic Gram-positive bacteria displaying antibiotic resistance have been isolated including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), glycopeptide intermediate-susceptible Staphylococcus aureus (GISA), vancomycin-resistant MRSA (VR-MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). Like VRE, therapeutic options for treating infections by these organisms are limited.
Resistance transfer is another complicating factor in the management of antibiotic-resistant infections. Vancomycin resistance can transfer from VRE to other Gram-positive bacteria, including S. aureus, in vitro. Thus, the presence of resistant bacteria (e.g., VRE) in a hospital poses not just the risk of infection but also the continued evolution of resistant organisms (e.g., creating more virulent organisms such as VR-MRSA).
A need exists to develop alternative strategies of antibacterial treatment. For example, there exists a need for new compositions and methods of treating or preventing bacterial infection (e.g., bacteremia) caused by strains of bacteria unsusceptible to current forms of antibacterial treatments (e.g., Gram-positive bacteria such as MRSA and VRE).